Hypericin Alleviate Depression Through Remodeling Gut Microbiota And Modulating The Serum Metabolism

Background:Hypericin has demonstrated protective effects on depression,however,the exact mechanisms remain unclear.Method:In this study,we established a depression mice model using chronic restraint stress(CRS)and provided treatment with 225 mg/kg hypericin after 3h CRS daily.The changes in gut microbiota post Hypericin treatment were then investigated using 16S rRNA sequencing.Additionally,serum untargeted metabolomics were performed to examine the metabolic regulations of Hypericin on depression.Then we did the correlation analysis between differential gut microbiota and differential serum metabolites.We also assessed hippocampal neuron damage,expression of serotonin system genes and inflammation in colon and hippocampus.And we further explored the mechanisms that influence glycerophospholipid metabolism through immunohistochemistry and western blotting.Results:Our results showed that Hypericin can reduce depression-like behavior and upregulate the serotonin level.Additionally,Nissl staining and HE staining showed that Hypericin treatment improved the neuron damage and alleviate the inflamamtion of hippocampus.Alcian staining and HE staining showed that hypericin increased the number of goblet cells and reduces inflammation in the colon.Hypericin downregulate the mRNA expression of infammatory cytokines(IL2、IL6、IFNy)in the colon and hippocampus.16s rRNA sequencing and untargeted metabolomics study showed that the gut microbiota community and serum metabolites of depressed mice were significantly changed.Akkermansia was significantly increased in the gut microbiota of CRS mice administered Hypericin,and the metabolites(Glycerophosphocholine;LysoPC(22:5(7Z,10Z,13Z,16Z,19Z);LysoPC(20:4(8Z,11 Z,14Z,17Z);LysoPC(18:0))in the glycerophospholipid metabolic pathway were also increased significantly.Correlation analysis showed that the regulation effect of hypericin on glycerophospholipid metabolism was positively correlated with the abundance changes of Akkermansia.The results of immunohistochemistry and Western blot showed that the expressions of 5-HT2BR and cPLA2 in the hippocampus and colon of mice were increased after administration of hypericin.Immunohistochemistry showed that 5-HT2BR and Cpla2 which is related to glycerophospholipid metabolism pathway was increased after Hypericin treatment.Conclusion:In conclusion,our study reveals that the ameliorative effect of Hypericin on depression may be mainly related to the increasing of Akkermansia in the gut and the regulation of body’s glycerophospholipid metabolic pathway.Hypericin may further exert the antidepressant effect of serotonin by up-regulating the expression of 5-HT2BR,and may regulate the metabolism of glycerophospholipid by up-regulating the expression of cPLA2,but the specific mechanism still needs to be further explored.